Methods for treating hyperactive gastric motility

ABSTRACT

This invention provides methods and pharmaceutical compositions for treating, inhibiting or preventing hyperactive gastric motility in a mammal utilizing agonists of KCNQ potassium channels, including KCNQ2, KCNQ3, KCNQ4 and KCNQ5 potassium channels, alone or in combination. The hyperactive gastric motility may be associated with maladies including, colitis, irritable bowel syndrome and Crohn&#39;s disease. Compounds useful in these methods include the 1,2,4-triamino-benzene derivatives described in U.S. Pat. No. 5,384,330 (Dieter et al.) and the substituted 3-phenyl oxindole compounds described in U.S. Pat. No. 5,565,483 (Hewawasam et al.).

[0001] This application is a divisional of U.S. application Ser. No.10/114,148 filed on Apr. 2, 2002, pending, which in turn claims thebenefit of U.S. Provisional application Serial No. 60/281,471, filedApr. 4, 2001. The entire disclosures of the Ser. Nos. 60/281,471 and10/114,148 applications are hereby incorporated by reference.

[0002] This invention relates to novel methods for modulating gastrictissues utilizing compounds which modulate the KCNQ family of potassiumchannels, particularly compounds which open or agonize the channels. Themethods of this invention include the treatment, prevention, inhibitionand amelioration of hyperactive gastric motility, including thatassociated with colitis, Irritable Bowel Syndrome and Crohn's Disease.

BACKGROUND OF THE INVENTION

[0003] U.S. Pat. No. 5,384,330 (Dieter et al.) teaches pharmacologicallyactive 1,2,4-triaminobenzene derivatives of the General Formula:

[0004] and their properties as anti-epileptic, muscle relaxing,fever-reducing and peripheral analgesic agents.

[0005] U.S. Pat. No.5,565,483 (Hewawasam et al.) teaches compounds ofthe formulae:

[0006] wherein: R is hydrogen, hydroxy or fluoro; R¹, R², R³ and R⁴ eachare independently hydrogen, C₁₋₄ alkyl, halogen, trifluoromethyl,phenyl, p-methylphenyl or p-trifluoromethylphenyl; or R¹ and R², R² andR³ or R³ and R⁴ are joined together to form a benzo fused ring; R⁵ ishydrogen or C₁₋₄ alkyl; and R⁶ is chlorine or trifluoromethyl; or anontoxic pharmaceutically acceptable salt, solvate or hydrate thereof,which are potassium channel openers useful for treating ischemia,convulsions and asthma.

[0007] The article Modulation of KCNQ2/3 Potassium Channels by the NovelAnticonvulsant Retigabine, Main et al., Molecular Pharmacology, 58: pp.253-262, 2000, describes the actions of retigabine (D23129;N-[2-amino-4-(4-fluorobenzylamino)-phenyl]carbamic acid ethyl ester) inmodulating the KCNQ2/3 potassium channels in oocytes in a 3-fold manner,i.e. retigabine shifts the voltage dependence of channel activation tomore hyperpolarized membrane potentials, increases the rate of channelactivation and slows channel deactivation.

[0008] U.S. Pat. Nos. 5,849,789 and 5,852,053 (both to Rostock et al.)teaches the use of retigabine for the treatment of neurodegenerativedisorders, including those associated with stroke.

[0009] U.S. Pat. No. 5,914,425 (Meisel et al.) teaches novel crystallineforms of retigabine.

[0010] U.S. Pat. No. 6,117,900 teaches the use of retigabine, also knownas N-[2-amino-4-(4-fluorobenzylamino)-phenyl]carbamic acid ethyl ester,for the treatment of neuropathic pain.

DESCRIPTION OF THE INVENTION

[0011] This invention comprises methods for treating, preventing,inhibiting, alleviating or controlling hyperactive gastric motility in amammal, the methods comprising administering to a mammal in need thereofa pharmaceutically effective amount of a compound which acts as anagonist or opener of the KCNQ family of potassium channels, includingthe KCNQ2, KCNQ3, KCNQ4, and KCNQ5 potassium channels, alone or incombination. A particular embodiment of this invention includes use inthe methods described herein of one or more agonists or openers ofKCNQ2/3 potassium channels. Another series of methods of this inventioncomprises use of one or more agonists or openers of KCNQ3/5 potassiumchannels. Further methods of this invention comprise treatment of thebladder instability conditions described herein by pharmaceuticaladministration of one or more agonists or openers of KCNQ4 potassiumchannels.

[0012] Specific methods of this invention include the treatment,prevention, inhibition, alleviation or control of hyperactive gastricmotility associated with colitis, irritable bowel syndrome (IBS) orCrohn's Disease.

[0013] Among the compounds useful in the methods of this invention arethose disclosed in U.S. Pat. No. 5,384,330 (Dieter et al.), the contentsof which are incorporated herein by reference. The compounds includethose of the formula:

[0014] wherein:

[0015] R₁ is selected from hydrogen, C₁-C₆-alkyl, C₂-C₆-alkanoyl or theradical Ar;

[0016] R₂ is selected from hydrogen or C₁-C₆-alkyl;

[0017] R₃ is selected from C₁-C₆-alkoxy, NH₂, C₁-C₆-alkylamino,C₁-C₆-dialkylamino, amino substituted by the radical Ar, C₁-C₆-alkyl,C₂-₆-alkenyl, C₂-C₆-alkynyl, the radical Ar or the radical ArO—;

[0018] R₄ is selected from hydrogen, C₁-C₆-alkyl or the radical Ar;

[0019] R₅ is selected from hydrogen or C₁-C₆-alkyl or the radical Ar;

[0020] Alk indicates a straight or branched alkylene group with 1-9carbon atoms, which can also be substituted by the radical Ar;

[0021] Ar is a phenyl radical substituted by the radicals R₆, R₇ and/orR₈ where these radicals R₆, R₇ and R₈ are the same or different andrepresent H, C₁-C₆-alkyl, C₃-C₇-cycloalkyl, hydroxy, C₁-C₆-alkoxy,C₂-C₆-alkanoyloxy, halogen, hydroxy, C₁-C₆-halogenoalkyl, —CN, —NH₂,—NH—C₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂, —CO₂H, —CO—C₁-C₆-alkyl,—CO—O—C₁-C₆-alkyl, —COAr, —CO—OAr, —CONH₂, —CONH—C₁-C₆-alkyl,—CON(C₁-C₆-alkyl)₂, —CONHAr, —NH—CO—C₁-C₆-alkyl, —NHCO—Ar,—NHCO—C₁-C₆-alkoxy, —N—H—CO—Ar, —NHCO—NH₂, —NHCO—N(—C₁-C₆-alkyl)₂,—NHCO—NHAr, —NH—SO₂—C-1-C₆-alkyl, —NH—SO₂Ar, —NH—SO₂-nitrophenyl,—SO₂—OH, —SO₂—C₁-C₆-alkyl, —SO₂—Ar, —SO₂—C₁-C₆-alkoxy, —SO₂—OAr,—SO₂—NH₂, —SO₂—NH—C₁-C₆-alkyl, —SO₂—N(C₁-C₆-alkyl)₂, —SO₂—NHAr,—SO₂—C₁-C₆-alkoxy;

[0022] n is 0 or 1;

[0023] or a pharmaceutically acceptable salt thereof.

[0024] The alkyl groups, halogenalkyl groups, alkenyl groups, alkynylgroups, alkoxy groups, alkylamino groups, alkanoyl amino groups,alkanoyloxy groups and alkanoyl groups in general can be straight orbranched. The same also applies to alkyl and alkyloxy groups (=alkoxygroups) if these are components of more complicated radicals for examplein the form of a monoalkyl- or dialkylamino group, alkanoylamino group,carbalkoxy group, alkylcarbonyl group and analogous groups. TheC₃-C₇-cycloalkyl group is preferably cyclopentyl or cyclohexyl.C₂-C₆-alkenyl preferably represents allyl. C₂-C₆-alkynyl preferablyrepresents propargyl.

[0025] The halogen atoms are chlorine, bromine or fluorine, inparticular chlorine of fluorine. The alkyl and alkoxy groups as such oras components of groups of more complicated radicals consist inparticular of 1-4 carbon atoms, preferably 1 or 2 carbon atoms. Alkanoylgroups, such as alkanoylamino groups or alkanoyloxy groups consist inparticular of 2-4, preferably 2-3 carbon atoms. Alk consists inparticular of 1-3, preferably 1 or 2 carbon atoms.

[0026] Among the more preferred compounds of this group are:

[0027] 2-Amino-4-(4-fluorobenzylamino)-1 -ethoxycarbonylaminobenzene;

[0028] 2-Amino-4-(4-trifluoromethylbenzylamino)-1-ethoxycarbonylamino-benzene;

[0029] 2-Amino-4-benzylamino-1 -ethoxycarbonylamino-benzene;

[0030] 2-Amino-4-(3,5-dichlorobenzylamino)-1-ethoxycarbonylaminobenzene;

[0031] 2-Amino-4-(3,5-dichlorobenzylamino)-1 -propyloxycarbonylaminobenzene;

[0032] 2-Amino-(2-chlorobenzylamino)-1-(diethylcarbamoylamino) benzene;

[0033] 2-Amino-4-(2,4-dichlorobenzylamino)-1-(dimethylcarbamoylamino)benzene; and

[0034] 1,2-Diacetylamino-4-(4-fluorobenzylamino) benzene;

[0035] Among the most preferred compounds for use in the methods of thisinvention are N-[2-amino-4-(4-fluorobenzylamino)-phenyl]carbamic acidand its pharmaceutically acceptable salts and ester forms. Of particularpreference is retigabine, also known asN-[2-amino-4-(4-fluorobenzylamino)-phenyl]carbamic acid ethyl ester (CASRegistry No. 150812-12-7), having the formula:

[0036] Also useful in the methods of this invention are the metaboliteforms of retigabine which may be isolated from blood, urine or feces ofrecipients of N-[2-amino-4-(4-fluorobenzylamino)-phenyl]carbamic acidethyl ester. The metabolites include the glucoside of retigabine,[4-(4-Fluoro-benzylamino)-2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydropyran-2-ylamino)-phenyl]-carbamicacid ethyl ester, as well as its two glucoronide analogs,6-[2-Ethoxycarbonylamino-5-(4-fluoro-benzylamino)-phenylamino]-3,4,5-trihydroxy-tetrahydro-pyran-2-carboxylicacid and6-[(3-Amino-4-ethoxycarbonylamino-phenyl)-(4-fluoro-benzyl)-amino]-3,4,5-trihydroxy-tetrahydro-pyran-2-carboxylicacid. Further metabolites includeN-[2-Amino-4-(4-fluoro-benzylamino)-phenyl]acetamide, its cyclizedanalog (4-Fluoro-benzyl)-2-methyl-1H-benzoimidazol-5-yl)amine and theglucoronide analogs ofN-[2-Amino-4-(4-fluoro-benzylamino)-phenyl]acetamide,6-[(4-Acetylamino-3-amino-phenyl)-(4-fluoro-benzyl)-amino]-3,4,5-trihydroxy-tetrahydro-pyran-2-carboxylicacid and6-(2-Acetylamino-5-(4-fluoro-benzylamino)-phenylamino]-3,4,5-trihydroxy-tetrahydro-pyran-2-carboxylicacid.

[0037] Also useful in the methods of this invention are the substituted3-phenyl oxindole compounds disclosed in U.S. Pat. No. 5,565,483(Hewawasam et al.), which issued on Oct. 15, 1996, the contents of whichare incorporated herein by reference. These compounds include thesubstituted 3-phenyl oxindole compounds having the formulae:

[0038] wherein:

[0039] R is hydrogen, hydroxy or fluoro;

[0040] R¹, R², R³ and R⁴ each are independently hydrogen, C₁₋₄ alkyl,halogen, trifluoromethyl, phenyl, p-methylphenyl orp-trifluoromethylphenyl; or R¹ and R², R² and R³ or R³ and R⁴ are joinedtogether to form a benzo fused ring;

[0041] R⁵ is hydrogen or C₁₋₄ alkyl; and

[0042] R⁶ is chlorine or trifluoromethyl;

[0043] or a nontoxic pharmaceutically acceptable salt, solvate orhydrate thereof.

[0044] One group of the substituted 3-phenyl oxindole compounds usefulwith this invention includes those described above wherein R ishydrogen. Another subgroup of these compounds include those in which R¹,R², R³ and R⁴ are each independently selected from H, C₁ to C₄ alkyl,halogen or trifluoromethyl, and when R¹ and R⁴ are H; R² or R³ isphenyl, p-methoxyphenyl or trifluormethylphenyl; or R¹ and R², R² andR³, or R³ and R⁴ are joined together to form a benzo fused ring; R5 is Hor C₁ to C₄ alkyl; and R⁶ is chlorine or trifluoromethyl, or apharmaceutically acceptable salt form thereof.

[0045] Non-limiting examples of these substituted 3-phenyl oxindolecompounds are:

[0046](±)-3-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)-2H-indol-2-one;

[0047](±)-3-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-6-(trifluoromethyl)-2H-indol-2-one;

[0048](±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)-2H-indol-2-one;

[0049](±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-6-(trifluoromethyl)-2H-indol-2-one;

[0050](±)-3-(5-Chloro-2-hydroxyphenyl)-4,6-dichloro-1,3-dihydro-3-hydroxy-2-H-indol-2-one;

[0051](±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-7-(trifluoromethyl)-2H-indol-2-one;

[0052](±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-4-trifluoromethyl)2H-indol-2-one;

[0053](±)-1,3-Dihydro-3-hydroxy-3-[2-hydroxy-5-(trifluoromethyl)phenyl]-6-(trifluoromethyl)-2H-indol-2-one;

[0054](±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-4,6-bis(trifluoromethyl)-2H-indol-2-one;

[0055](−)-3-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)-2H-indol-2-one;

[0056](±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)2H-indol-2-one;

[0057](−)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)2H-indol-2-one;

[0058](±)-3-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)2H-indol-2-one;

[0059](±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-2H-benz[g]indol-2one;

[0060](±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-6-phenyl-2H-indol-2-one;

[0061](±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-2H-benz[g]indol-2-one;

[0062](±)-3-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-phenyl-2H-indol-2-one;

[0063](±)-3-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-iodo-2H-indol-2one;

[0064](±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-6-(4-methylphenyl)-2H-indol-2-one;

[0065](±)-3-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-7-(trifluoromethyl)-2H-indol-2-one;

[0066](±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-2H-benz[e]indol-2-one;

[0067](±)-3-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-5-methyl-2H-indol-2-one;

[0068](±)-3-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-4,6-bis(trifluoromethyl)-2H-indol-2-one;

[0069](±)-5-Bromo-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-2H-indol-2one;

[0070](±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-6-[4-(trifluoromethyl)phenyl]-2H-indol-2-one;

[0071] (±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-2H-indol-2-one;

[0072](±)-5-Bromo-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-hydroxy-2H-indol-2-one;

[0073](±)-3-(5-Chloro-2-hydroxyphenyl)-4,6-dichloro-1,3-dihydro-2H-indol-2-one;

[0074](±)-3-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-hydroxy-6-iodo-2H-indol-2-one;

[0075] (±)-3-(5-Chloro-hydroxyphenyl)-1,3-dihydro-6-iodo-2H-indol-2-one;

[0076](±)-3-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-hydroxy-2H-benz[f]indol-2one;

[0077](±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-2H-benz[f]indol-2one;and

[0078](±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-2H-benz[f]indol-2-one;

[0079] and the pharmaceutically acceptable salt forms thereof.

[0080] Among the more preferred compounds of this group are:

[0081](±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-6-(trifluoromethyl)-2H-indol-2-one;

[0082](±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)-2H-indol-2-one;

[0083](±)-3-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indol-2-one;

[0084](±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-2H-benz[g]indol-2-one;

[0085](±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-6-phenyl-2H-indol-2-one;and

[0086](±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-2H-benz[e]indol-2-one.

[0087] Pharmaceutically acceptable salt forms of these substituted3-phenyl oxindole compounds include those formed as base addition,including those formed using suitable inorganic bases, such as alkaliand alkaline earth metal bases, such as sodium, potassium, magnesium andcalcium metallic cations. The compounds may be administered as describedin U.S. Pat. No. 5,565,483. A pharmaceutically effective amount inmammals, including man, may be from about 0.1 pg/kg to about 100 mg/kgof body weight. Parenteral administration may be completed at aneffective dose of from about 1 pg/kg to about 10 mg/kg of body weight.

[0088] The methods of this invention are useful for treating,preventing, inhibiting or ameliorating hyperactive gastric motility in amammal, the methods each comprising administering to a mammal in need ofsuch treatment a pharmaceutically effective amount of a KCNQ potassiumchannel opener, as described above. The conditions which may be treatedwith the methods of this invention include irritable bowel syndrome,also known as spastic colon, Crohn's Disease and mucous colitis. Themethods of this invention may also be used for mammaliangastrointestinal (GI) conditions including diarrhea, chronic diarrhea,acute diarhea, abdominal pain associated with diarrhea, postprandialurgency, postprandial accentuation of diarrhea or abdominal pain, or acombination of two or more of these symptoms.

[0089] Irritable Bowel Syndrome (IBS) is part of a spectrum of diseasesknown as Functional Gastrointestinal Disorders, which include diseasessuch as noncardiac chest pain, nonulcer dyspepsia, and chronicconstipation or diarrhea. It has also been referred to as spastic colon,nervous colitis, mucous colitis, functional colitis or colonic neurosis.As no diagnostic marker is currently associated with IBS, the diagnosisis one of exclusion based on symptoms. Manning et al. first reported sixsymptoms which differentiated IBS from other gastrointestinal diseases.These criteria have become art recognized in the diagnosis of IBS, seeGut 1990; 31: 77-81; Olibuyide et al., Dig Dis Sci 1995; 40:983-5; Raoet al., J Assoc Physician India 1993;41:357-8; and Jeong et al. KoreanJ. Intem. Med. 1993;8:34-9. The six ‘Manning Criteria’ are: a) relief ofabdominal pain with defecation, b) looser stools with the onset of pain,c) more frequent bowel movements at onset of pain, d) abdominal bloatingor distention, e) feelings of incomplete evacuation, and f) passage ofmucus per rectum. Generally speaking, the more ‘Manning Criteria’present the more likely an indication of IBS.

[0090] The compounds and methods of this invention may be used inconjunction with laxatives and anti-diarrheal medications frequentlyused for the treatment or amelioration of symptoms of IBS. In patientswith abdominal cramps, antispasmodic drugs, such as dicyclomine, may beused with the methods herein. It will also be understood that the KCNQchannel opening compounds of this invention may be administered inconjunction with conventional drug therapies for IBS, including opioidagonists such as loperamide or anticholinergic agents, such aspepenzolate bromide or timepidium bromide to control gastrointestinalhypermotility. In cases where anxiety or related conditions increase thelikelihood or severity of symptoms, anti-anxiety agents may beco-employed. These include those known in the art, but not limited tovenlafaxine HCl, diazepam, fluoxetine HCl, hydroxyzine HCl, hydroxyzinepamoate, mephobarbital, meprobamate, paroxetine HCl, doxepin HCl,lorazepam, chlordiazepoxide HCl, alone or in combination withamitryptyline HCl, clorazepate dipotassium, or alprazolam. Each of thesemedicaments may be administered in the conventional methods andadministrations known in the art, including those described in thePhysicians' Desk Reference 2001, 55 Edition, published by MedicalEconomics Company, Inc. at Montvale, N.J. 07645-1742.

[0091] At the recommendation of a medical professional, non-medicationand lifestyle changes may also be recommended for IBS sufferers,including an increase in fiber intake (dietary or fiber supplements) tohelp relieve constipation and cramps.

[0092] Crohn's disease involves chronic inflammation of the intestineswith symptoms including abdominal pain, diarrhea, and weight loss. Lesscommon symptoms include poor appetite, fever, night sweats, rectal pain,and rectal bleeding. Crohn's disease may affect the colon, the rectum,and the small intestine and, in rare instances, also the stomach, mouth,and esophagus. Crohn's colitis is inflammation that appears only in thecolon, often involving abdominal pain and bloody diarrhea. Anal fistulaeand perirectal abscesses can also occur. Crohn's enteritis isinflammation confined to the small intestine. Crohn's terminal ileitisis inflammation that affects the end of the small intestine (terminalileum). Crohn's enterocolitis and ileocolitis involves inflammation ofboth the small intestine and the colon. Crohn's terminal ileitis andileocolitis are the most common types of Crohn's disease. Abdominal painand diarrhea often result in each type of Crohn's disease. The compoundsand methods of this invention may be used to treat, inhibit, prevent orameliorate each of these Crohn's conditions.

[0093] The compounds of this invention may also be used in combinationtherapies or regimens with medications conventionally used to treatCrohn's disease and its symptoms including anti-inflammatory agents,such as 5-ASA compounds, systemic corticosteorids, topicalcorticosteroids, and antibiotics, as well as immunomodulators.Anti-inflammatory agents which are effective in treating Crohn's diseaseinclude corticosteroids and the 5-aminosalycylates (5-ASA) compounds.Examples of corticosteroids include Prednisone, Prednisolone, andBudesonide. Examples of 5-ASA compounds include ASACOL® brandmesalamine, PENTASA® brand mesalamine controlled release capsules, andROWASA® brand mesalamine rectal suspensions enema. Antibiotics may beused in conjunction to the potassium channel openers of this inventionfor treating Crohn's colitis, such as metronidazole (available asFLAGLYL® brand metronidazole tablets or FLAGLYL® ER brand extendedrelease metronidazole tablets) and ciprofloxacin. Examples of usefulimmunomodulators include 6-mercaptopurine (6-MP), azathioprine,methotrexate, and anti-TNF-alpha (REMICADE® infliximab recombinant forIV injection).

[0094] In cases where diseased portions of the intestines are surgicallyremoved Crohn's disease may eventually return to previously healthytissue. The KCNQ potassium channel openers of this invention may be usedin conjunction with medications such as mesalamine or 6-mercaptopurine(6-MP) to reduce the chances of Crohn's disease relapse after surgery orlimit the severity of such relapses.

[0095] In relevant diarrhea-related conditions, a medical professionalmay also use the KCNQ channel openers of this invention in combinationwith an inhibitor of gastric secretion, such as a proton pump inhibitor,a histamin H₂-receptor blocker, omeprazole, lansoprazole, cimetidine,ranitidine, nizatidine, or famotidine.

[0096] Pharmaceutically effective amounts of the KCNQ channel openingcompounds described herein may also be used to inhibit, limit or delaydefecation in a mammal in need of such treatment. This may be used toinhibit or control anal incontinence in a mammal, including humans, whoexperience a lessened ability to control bowel movements or experienceor are susceptible to anal incontinence. These methods include effectinga desirable delay or inhibition of postprandial urgency or postprandialintestinal cramping or related pain.

[0097] The methods of this invention are useful for inducing orassisting in control or prevention or treatment of the maladiesdescribed herein in humans in need of such relief, including adult andpediatric uses. However, they may also be utilized for veterinaryapplications, particularly including canine and feline fecal controlmethods. If desired, the methods herein may also be used with farmanimals, such as ovine, bovine, porcine and equine breeds.

[0098] The applications may utilize conventional oral, rectal,parenteral or intravenous delivery methods as conventionally utilized inveterinary practice. Most preferable in most instance for home use withcompanion animals are oral tablets or capsules or neat compound orpowdered or granular pharmaceutical formulations which may be mixed withchewable or liquid veterinary formulations or food materials or liquidsacceptable to the animal in question.

[0099] As used herein, the terms “pharmaceutically effective amount” or“therapeutically effective amount” mean the total amount of each activecomponent of the pharmaceutical composition or method that is sufficientto show a meaningful patient benefit, i.e., treatment, prevention oramelioration of hyperactive gastric motility or the excessive orundesirable urge to defecate, or a decrease in the frequency ofincidence of fecal incontinence. When the malady in question warrants, apharmaceutically or therapeutically effective dose may be considered theminimal amount of the compound in question which will alleviate, inhibitor remove the cramping, pressure, pain or feeling of fecal urgencyassociated with hyperactive gastric motility. When applied to anindividual active ingredient, administered alone, the term refers tothat ingredient alone. When applied to a combination, the term refers tocombined amounts of the active ingredients that result in thetherapeutic effect, whether administered in combination, serially orsimultaneously.

[0100] The methods of this invention may be accomplished with a dailydose of the active compounds described above from U.S. Pat. No.5,384,330 of from about 0.1 mg/kg to about 10 mg/kg. Doses may beadministered as a single regimen, such as only prior to bedtime orbefore travel, or as a continuous regimen divided by two or more dosesover the course of a day. Human administration may be at dosages of fromabout 10 mg BID to about 1000 mg BID, preferably from about 50 mg BID toabout 500 mg BID, more preferably at a dose of from about 100 mg BID toabout 300 mg BID.

[0101] Compounds as described in U.S. Pat. No. 5,384,330, includingretigabine, can be administered orally using conventional pharmaceuticalexcipients or carriers, preferably coated or contained in hard or softgelatin capsules. Examples of oral formulations contained in hardgelatin capsules can include those in which the active compoundcomprises from about 45% to 50%, by weight, of the formulation.Microcrystalline cellulose comprises from about 43% to about 47%,povidone comprises from about 3% to about 4%, and silicon dioxide andmagnesium stearate each comprise from about 0.3% to about 0.7%, each byweight. Specific examples of capsules containing 50 mg, 100 mg and 200mg may be formulated utilizing the following lists of components.Ingredient Amount/Capsule 50 mg Retigabine Capsules Retigabine 50.0 mgMicrocrystalline Cellulose, NF 45.5 mg Povidone, USP 3.5 mg SiliconDioxide, Colloidal, anhydrous, NF 0.5 mg Magnesium Stearate, EP 0.5 mgTheoretical Fill Weight 100 mg 100 mg Retigabine Capsules Retigabine100.0 mg Microcrystalline Cellulose, NF 91.0 mg Povidone, USP 7.0 mgSilicon Dioxide, Colloidal, anhydrous, NF 1.0 mg Magnesium Stearate, EP1.0 mg Theoretical Fill Weight 200 mg 200 mg Retigabine CapsulesRetigabine 200.0 mg Microcrystalline Cellulose, NF 182.0 mg Povidone,USP 14.0 mg Silicon Dioxide, Colloidal, anhydrous, NF 2.0 mg MagnesiumStearate, EP 2.0 mg Theoretical Fill Weight 400 mg

[0102] The ingredients in the formulations above can be prepared usingthe following steps.

[0103] 1 ) Weigh separately the active ingredient (retigabine),preferably screened through an 800 micron screen, and themicrocrystalline cellulose components.

[0104] 2) Prepare a granulation solution by dissolving the Povidone, USPin purified water.

[0105] 3) Place the ingredients from Step 1 into a suitable blender andmix thoroughly.

[0106] 4) Screen the mixture from Step 3 through a 1000 μm screen andplace the screened mixture into the vessel of a fluidized bedgranulator.

[0107] 5) Heat the ingredients in the fluid bed granulator up to 27° C.product temperature while mixing.

[0108] 6) Add the granulation solution from Step 2 to the fluid bed.

[0109] 7) Dry the granulate in the fluid bed.

[0110] 8) Weigh the colloidal silicon dioxide component, preferablyscreened through a 1000 μm screen, and the magnesium stearate component,preferably screened through a 600 μm screen.

[0111] 9) Add the silicon dioxide and magnesium stearate components tothe fluid bed granulator's vessel containing the dried granulate fromStep 7 and mix the components thoroughly.

[0112] 10) Screen the mixed components from Step 9, preferably through a800 μm screen.

[0113] 11) Transfer the final screened components into a suitableblender and mix thoroughly.

[0114] The final component mixture from Step 11 can then be coated,encapsulated or compressed into tablets utilizing conventional tabletexcipients or carriers, as desired. It will be understood that oraldosage forms within the scope of this invention can be prepared usingthe components listed above in respective amounts according the dose ofactive ingredient in the particular formulation. For veterinary uses,the final mixture of Step 11 can be administered neat or mixed intofoods acceptable to the animal in question. Further, the mixtures can beformulated into tablets, capsules or coated products, as describedabove, or integrated into conventional veterinary medicaments or foodproducts.

[0115] For intravenous administration, the compounds from U.S. Pat. No.5,384,330 described herein may be prepared and maintained inconventional lyophylized formulations and reconstituted prior toadministration with an intravenously acceptable saline solution, such asa 0.9% saline solution. The pH of the intravenous formulation can beadjusted, as needed, with an intravenous and pharmaceutically acceptableacid, such as methanesulfonic acid.

[0116] The following demonstrates the ability of retigabine to open KCNQpotassium channels in mammalian tissue.

[0117] KNCQ1, 3 and 5 Expression and M-Current Activity in Rat UrinaryBladder

[0118] Using quantitative rtPCR, the expression of KCNQ1, KCNQ3 andKCNQ5 potassium channels was identified in the rat urinary bladder. Thehighest levels of expression were seen in KCNQ5 (0.2±0.1 ng KCNQ5mRNA/GAPDH mRNA). To further probe M-current activity in the bladder,retigabine (10 μM, M-current agonist) was tested in isolated bladdersmooth muscle cells using standard patch-clamp techniques. Exposure toretigabine significantly increased an outward current that wasinsensitive to iberiotoxin and was associated with a membranehyperpolarization of 17.8±3.0 mV (n=5). This hyperpolarization wasreversed by the addition of linopirdine (50 μM an M-current antagonist)to the tissue bath. Retigabine relaxed isolated carbachol contracted ratbladder strips with an IC₅₀ of 3.5±0.9 μM (n=14). This relaxation wasreversed by the M-current blockers linopirdine and XE-991.

[0119] KCNQ Potassium Channel Activity in Guinea Pig Ileum

[0120] Following the procedures of the previous example, the effects ofretigabine on isolated precontracted guinea pig ileum preparations werestudied. Sections of ileum were isolated from male guinea pigs andsuspended in a tissue bath. One end of the tissue was anchored to thebottom of the bath, and the other end to a force transducer. Tissueswere contracted with either 20 mM KCl or 200 nM carbachol. The KCNQchannel agonist retigabine was added to the tissue baths in increasingconcentrations. Retigabine produced a concentration-dependent inhibitionof contraction as follows:

[0121] Both responses to retigabine were antagonized by the KNCQ channelblocker XE-991.

What is claimed:
 1. A method of treatment or inhibition of hyperactivegastric motility in a mammal, the method comprising administering to amammal in need thereof a pharmacologically effective amount of acompound of the formula:

wherein: R is hydrogen, hydroxy or fluoro; R¹, R², R³ and R⁴ each areindependently hydrogen, C₁₋₄ alkyl, halogen, trifluoromethyl, phenyl,p-methylphenyl or p-trifluoromethylphenyl; or R¹ and R², R² and R³ or R³and R⁴ are joined together to form a benzo-fused ring; R⁵ is hydrogen orC₁₋₄ alkyl; and R⁶ is chlorine or trifluoromethyl; or a nontoxicpharmaceutically acceptable salt, solvate or hydrate thereof.
 2. Themethod of treatment claim 1 wherein the compound is selected from:(±)-3-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)-2H-indol-2-one;(±)-3-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-6-(trifluoromethyl)-2H-indol-2-one;(±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)-2H-indol-2-one;(±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-6-(trifluoromethyl)-2H-indol-2-one;(±)-3-(5-Chloro-2-hydroxyphenyl)-4,6-dichloro-1,3-dihydro-3-hydroxy-2-H-indol-2-one;(±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-7-(trifluoromethyl)-2H-indol-2-one;(±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-4-trifluoromethyl)2H-indol-2-one;(±)-1,3-Dihydro-3-hydroxy-3-[2-hydroxy-5-(trifluoromethyl)phenyl]-6-(trifluoromethyl)-2H-indol-2-one;(±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-4,6-bis(trifluoromethyl)-2H-indol-2-one;(−)-3-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)-2H-indol-2-one;(±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)2H-indol-2-one;(−)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)2H-indol-2-one;(±)-3-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)2H-indol-2-one;(±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-2H-benz[g]indol-2one;(±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-6-phenyl-2H-indol-2-one;(±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-2H-benz[g]indol-2-one;(±)-3-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-phenyl-2H-indol-2-one;(±)-3-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-iodo-2H-indol-2one;(±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-6-(4-methylphenyl)-2H-indol-2-one;(±)-3-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-7-(trifluoromethyl)-2H-indol-2-one;(±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-2H-benz[e]indol-2-one;(±)-3-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-5-methyl-2H-indol-2-one;(±)-3-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-4,6-bis(trifluoromethyl)-2H-indol-2-one;(±)-5-Bromo-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-2H-indol-2one;(±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-6-[4-(trifluoromethyl)phenyl]-2H-indol-2-one;(±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-2H-indol-2-one;(±)-5-Bromo-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-hydroxy-2H-indol-2-one;(±)-3-(5-Chloro-2-hydroxyphenyl)-4,6-dichloro-1,3-dihydro-2H-indol-2-one;(±)-3-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-hydroxy-6-iodo-2H-indol-2-one;(±)-3-(5-Chloro-hydroxyphenyl)-1,3-dihydro-6-iodo-2H-indol-2-one;(±)-3-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-hydroxy-2H-benz[f]indol-2one;(±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-2H-benz[f]indol-2one;or (±)-3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-2H-benz[f]indol-2-one;or a pharmaceutically acceptable salt form thereof.
 3. The method ofclaim 1 wherein the mammal is a human.
 4. The method of claim 1 whereinthe mammal is feline or canine.
 5. The method of claim 1 wherein thehyperactive gastric motility in a mammal is associated with inflammatorybowel disease.
 6. The method of claim 1 wherein the hyperactive gastricmotility in a mammal is associated with Crohn's disease.